Compositions and method for treating symptoms of inflammation, pain and fever



United States Patent 3,228,831 CUMPOSITIONS AND METHOD FOR TREATINGSYMPTOMS 0F INFLAMMATION, PAIN AND FEVER John Stuart Nicholson andStewart Sanders Adams, Nottingham, England, assignors to Boots Pure DrugCompany Limited, Nottingham, England, a British company No Drawing.Filed Jan. 22, 1962, Ser. No. 167,941 Claims priority, application GreatBritain, Feb. 2, 1961, 3,999/61 12 Claims. (Cl. 167-53) This inventionrelates to phenylalkane derivatives. More particularly it relates tonovel pharmaceutical and veterinary compositions which comprise as theactive ingredient one or more members of a specified group ofderivatives of toluene. The invention also relates to the provision ofnovel members of this specified group of compounds. In another aspect,the invention relates to the treatment of diseases in animals.

It is an object of the invention to provide therapeutic compositions forthe relief of pain, fever and inflammation in animals which do notsuffer from the disadvantages of similar therapeutic compositions basedon aspirin, phenylbutazone or adrenocorticosteroids.

We have now discovered that compounds of the genwherein R representsethyl, propyl, butyl (except n-butyl), alkylene (C C pentyl (exceptn-pentyl), alkoxy (C C allyloxy, phenoxy, phenylthio or cycloalkyl (C -Coptionally substituted by alkyl (C -C in the 1-position, R representshydrogen or methyl and X represents the radical COOR wherein Rrepresents hydrogen or alkyl (C -C optionally substituted, COOM whereinM represents the ammonium ion or a single equivalent of a nontoxicmetallic cation, COOH.B wherein B represents a non-toxic organic base,CONH, CHO, CH NH or the group CH OR where R represents hydrogen or loweralkanoyl (C -C have valuable anti-inflammatory, analgesic andantipyretic properties.

Furthermore in general the compounds exhibit low toxicity and lowirritancy to the gastric mucosa, they do not have other undesirablepharmacological activities which might give rise to unwanted sideeffects and they are stable in the presence of water.

According to the present invention there are provided therapeuticcompositions comprising as active ingredient one or more compounds ofthe general formula I in association with a pharmaceutically acceptablediluent or carrier.

The following compounds are typical of the active compounds of thegeneral Formula I, but do not limit the invention in any way:

4-n-propylphenylacetic acid 4-ethoxyphenylacetic acid4-n-isopropylphenylacetic acid 4-propoxyphenylacetic acid4-isopropoxyphenylacetic acid 4-s-butylphenylacetic acid4-allyloxyphenylacetic acid 4-t-butylphenylacetic acid4-cyclopentylphenylacetic acid 4-isobutylphenylaoetic acid4-cycloheptylphenylacetic acid 4-cyclohexylphenylacetic acid 4-l-ethylpropyl phenylacetic acid 4-phenoxyphenylacetic acid 4-( l,2-dimethylpropy1) phenylacetic acid 4-phenylthiophenylacetic acidu-(4-cyclohexylphenyl) propionic acid 2- (4-isobutylphenyl)ethanol 2-(4-cyclohexylpheny1) ethanol 4-vinylphenylacetic acid 2-4-isopentylphenyl propanol 4-( l-methylcyclohexyl) phenylacetaldehydeAmmonium 4-t-butylphenylacetate 4-t-butylphenylacetamide 2-(4-cyclohexylphenyl propanol 4-isobutylphenylacetaldehyde 4-2,2-dimethylpropyl phenylacetic acid Octyl 4-t-butylphenylacetate 4-l-methylcyclohexyl phenylacetic acid Octyl a- (4-cyclohexylphenylpropionate 4-( l-ethylcyclohexyl phenylacetic acid Ethyl4-t-buty1phenylacetate 4-(2-methylbutyl) phenylacetic acid 41-4-isobutylphenyl propionaldehyde Sodium u-(4-cyclohexylphenyl)propionateoc- (4 cyclohexylphenyl propionaldehyde Methyl 4-t-butylphenylaoetateSodium 4-t-butylphenylacetate n-Propyl a-(4-isopentylphenyl) propionateButyl 4-t-butylphenylacetate Isopropyl 4-t-butylphenylacetatea-(4-isopentylphenyl)propionaldehyde n-Propyl 4-t-butylphenylacetate 2-(4-t-butylphenyl) ethanol 2-(4-butylphenyl)ethyl propionate2-(4-isobutylphenyl) propanol oc- 4-isobutylphenyl propionic acid4-t-pentylphenylacetic acid 2,4'-( l-methylcyclohexyl) phenyl ethanol 2-(4-isopentylphenyl) ethanol Ethyl-4-isobutylphenylacetate Benzylamine4-t-butylphenylacetate a-(4-t-butylphenyl) propionic acid4-isopentylphenylacetaldehyde uc- (4-isopentylphenyl) propionic acid2-4-t-butylphenylethylamine Ethyl a-(4-isobutylphenyl)propionaten-Propyl 4-isopentylphenylacetate a-(4-s-butylphenyl) propionic acida-4- l-ethylpropyl phenylpropionic acida-4-(Z-methylbutyl)phenylpropionic acid a-4-(2,2-dimethylpropyl)phenylpropi-onic acid 4-t-butylphenylacetaldehyde a-4'-l-ethylcyclohexyl phenylpropionic acid a- (4-ethylphenyl propionic acid.

According to the present invention there is also provided a method oftreating inflammation, pain and fever in animals by administering acomposition, comprising as active ingredient, one or more of thecompounds of general Formula I.

We have discovered that the compounds which are the active components ofthe compositions of the present invention are superior toacetylsalicyclic acid in that they exhibit one or more of the followingadvantages:

(a) They are less toxic;

(b) They have a higher therapeutic ratio;

(c) They are more stable in the presence of water or Water vapour;

((1) They are more soluble in water.

The alkali metal and alkaline earth metal salts of the acids areparticularly soluble in Water and they are valuable for the preparationof oral compositions.

The active compounds of the present invention may be prepared by methodswhich are well known for the prep- B II wherein R is butyl (exceptn-butyl), pentyl (except npentyl), cyclohexyl (optionally substituted byalkyl (C -C in the 1-position) or cycloheptyl; R is hydrogen or methyl;X is COOH, COOR (R =C C CHO, CH OH and the inorganic and organic saltsof the acids, provided R is not t-butyl or unsubstituted cyclohexyl whenR is hydrogen and X is COOH or CH OH and provided R is not ethyl when Ris hydrogen and R is s-butyl, t-butyl or t-pentyl.

A list of methods suitable for preparing these compounds is given below.In these representations R and R are as hereinbefore defined for generalFormulae I and II and Ph represents phenyl or phenylene.

ACIDS R Ph R1Ph.C 0.011; R1Ph.CHz.COOH

AlCla EtzCH M R Ph.CHz.COOEt R1Ph.CH(CO 0 E02 NaOEt NaOEt hydrolyseR1Ph.0Me(C O 0131;

decal'boxylate R Ph.CMe(C O OH): R1Ph.CH.C O OH t hydrolyse R1Ph.?H.C 0OR; R1Ph.(;JH.C O OH (R is alkyl, aryl, or aralkyl) COCLCOOR t MeMgBRlPh ZR;Ph.CO.GO OR R1Ph.C (OE).C 0 OR hydrolyse I CH3 CH3 CH3 (R isalkyl) Where these processes produce novel RiPh.COCHa HON HI/P R1Ph.CIl(CHLOE: R1Ph.CH.O O OH (11) Alcohols and aldehydes may be oxidised tothe corresponding acids.

ESTERS COOLGOOR H RlPh RiPh.CO.COOIR. R1Ph.CHz.COOR

R1Ph.CH.COOR

MeI R1Ph.?H.C 00R RlPh-CHNE.C 0 OR dehydrogenate R! -(|]H.CO 0 Etm-Qortooom.

RiPhlEH. C O OH dialklamlnoalkyl halide dialkylaminoalkyl esterhydrochloride (R is alkyl or where possible substituted alkyl e.g.

diethylarninoethyl) ALCOHOLS RiPh RPhCl E thylene oxide R1Ph.Mg.C1 RPh.CHzCHzCH (2) R Ph. $11.0 0 OR; hydrogenation R:

R1Ph.(IJH.CH1OH (R is H or alkyl) The hydrogenation takes place in thepresence of catalysts e.g. LiAlH or the ester is reduced with sodium tothe alcohol (Bouveault-Blanc reaction).

The conversion of the Grignard compound to the aldehyde may be carriedout by any of the known methods using e.g. HC(OEt) Ph.N=CH.OEt,Ph.NMe.OCH.

This conversion may be carried out using the known methods, e.g. usingKCN followed by HCl, the Rosenmund reaction, hydrogenation in thepresence of lithium tributoxyalumino hydride at 70 C, or the MacFadyen,Stephens reaction.

alkali R1Ph.CI) -CH.COOEt RiPh.CH.CHO CH3 CH3 (5) Other methods ofmaking aldehydes have been described by:

(a) Sonn and Miiller; Ben, 1919, 52, 1927.

(b) Fieser, Joshel and Seligman; J.A.C.S., 1939, 61, 1774. (c) Davies,Hodgson; J., 1943, 282.

(d) Lecomte, Dufour; Compt. rend, 1952, 234, 1887. (e) Leanze et al.;J'.A.C.S., 1954, 76, 1691.

(f) Kornthum et al.; J.A.C.S., 1959, 81, 41 13.

(g) Wolfram, Karabinos; J.A.C.S., 1946, 68, 1455. (h) Stephen method;J., 1925, 127, 1874.

(i) Brown et al.; Tetrahedron letters, 1959, 3, 9.

(j) Brown, Tsukamoto; I.A.C.S., 1959, 81, 502.

(k) Weygard; Angew Chem., 1953, 65, 525.

(1) Reid, Konigstein; Angew Chem, 1958, 70, 165. (m) Brown, Tsukamoto;J.A.C.S., 1961, 53, 2016.

(n) Levine; J.A.C.S., 1958, 80, 6150.

The salts of the acids can be made by reacting the acids with organic orinorganic bases.

The pharmaceutically acceptable diluents or carriers which are admixedwith the active compound to form the compositions of this invention arewell-known and the actual excipients which are used depend inter alia onthe method of administering the compositions. The compositions of thisinvention may be adapted for oral, topical or parenteral use but thepreferred method of administration is per os. In this case the oralcompositions may take the form of capsules, tablets, lozenges oreffervescent, granules, or liquid preparations such as mixtures,elixirs, syrups or suspensions, all containing one or more compounds ofthe aforementioned general formula; such preparations may be made bymethods well-known in the art.

The diluents which may be used in the preparation of such compositionsinclude those solid and liquid diluents which are compatible with theactive ingredients together with colouring matter and fiavouring ifdesired. We have found that a tablet containing the active ingredient inthe form of a salt in association with maize starch as a diluent is aparticularly valuable and convenient composition. Such tabletsdisintegrate rapidly in the stomach and generally do not set up gastricirritation.

The compositions of the invention in the form of effervescent granulesmay comprise a compound of the above general formula in association witha combination of effervescing agents well-known in the art. Such aneffervescent combination may include for example sodium bicarbonate inassociation with a free acid or acid salt such as tartaric acid orsodium acid tartrate.

The liquid compositions of the invention adapted for oral use may be inthe form of solutions or suspensions. Such compositions in the form ofsolutions may be aqueous solutions of a soluble compound of the abovegeneral formula in association with, for example, sucrose to provide asyrup. The composition in the form of suspensions may comprise aninsoluble compound of the present invention in association with watertogether with a suspending agent, fiavouring agents, colouring matter,etc.

The compositions of the invention which are adapted for topical useinclude ointments, creams and lotions containing compounds of the abovegeneral formula or their derivatives. Suitable ointments and creams maybe water miscible or water immiscible in character and include emulsionsprepared from emulsifying waxes and oils and also those prepared fromWater miscible polyethylene glycols. The lotions according to theinvention may comprise a solution of the active ingredients of the abovegeneral formula in a suitable liquid solvent diluent which is preferablya lower aliphatic alcohol which may contain a small proportion of water.

The active ingredients of the present invention may also be incorporatedinto the novel compositions with other known therapeutically activecompounds.

The screening test which was used to detect anti-inflammatory activitywas that described by Adams and Cobb, Nature, 181, 773, 1958.

Analgesic and antipyretic properties of the compounds were also assessedas were their toxicities on several types of animals, namely mice, rats,guinea pigs, cats and dogs. As is to be expected, the relativeactivities varied widely.

The evidence is that like aspirin the compounds of the present inventionare useful in the treatment of (a) painful inflammation of the jointsand periarticular tissues as occurs in rheumatoid arthritis, Stillsdisease and osteoarthritis; (b) various types of non-specificinflammatory or rheumatic conditions affecting the fibromuscular tissuesand connective tissue; (0) rheumatic fever and its sequelae.

The following non-limitative examples illustrate the invention:

Example 1 4-isobutylacetophenone (49.4 g.), sulphur (13.6 g.) andmorpholine (38 ml.) were refluxed for 16 hours; concentratedhydrochloric acid (344 ml.) and glacial acetic acid (206 ml.) were addedand the mixture was refluxed for a further 7 hours. The mixture wascooled, diluted with water and the oil which separated was isolated withether. The ethereal solution was extracted into aqueous sodium carbonatefrom which the crude acid was precipitated by addition of hydrochloricacid. The crude acid was again isolated with ether, the solution Washedwith water and evaporated to dryness to give a crystalline residue. Theresidue was crystallised from light petroleum (B.P. 40- 60 C.) to give4-isobutylphenylacetic acid M.P. 85.5- 87.5 C. Found: C, 75.1; H, 8.5. CH O requires C, 75.0; H, 8.3%.

The following compounds were made by the same method:

4-cycloheptyl phenylacetic acid M.P. 90.5-92.5 C. (Found: C, 77.3; H,8.7. C H O requires C, 77.6; H, 8.6%.)

4-(l-ethylpropyl)phenylacetic acid B.P. 153-154 C./2.5 mm. (Found: C,75.4; H, 8.6. C H O requires C, 75.8; H, 8.7%.)

4-(1,2-dimethylpropyl)phenylacetic acid B.P. 156-7" C./ 2.5 mm. (Found:C, 75.5; H, 8.6. C H O requires C, 75.8; H, 8.7%.)

4-(2,2-dimethylpropyl)phenylacetic acid M.P. 110.5-

11l C. (Found: C, 75.6; H, 8.5. C H O requires C, 75.8; H, 8.7%.)

4-(Z-methylbutyl)phenylacetic acid M.P. 38-40 C. (Found: C, 75.5; H,8.7. C H O requires C, 75.8; H, 8.7

4-(l-methylcyclohexyl)phenylacetic acid B.P. 194-6 C./ 3 mm. (Found: C,77.8; H, 8.4. C H O requires C, 77.6; H, 8.6%.)

4-(l-ethylcyclohexyl)phenylacetic acid, B.P. 188/0.7 mm. (Found: C,77.5; H, 8.2. G -H requires C, 78.0; H, 8.9%.)

4-isopentylphenylacetic acid, M.P. 62.5-63.5 C. (Found: C, 76.6; H, 8.6.C H O requires C, 75.8; H, 8.7

4-( 1-methylbutyl)phenylacetic acid, B.P. 114/ 1.5 mm. (Found: C, 75.4;H, 8.6. C H O requires C, 75.8; H, 8.7%.)

Example 2 4-s-butylacetophenone (40 g.) sulphur (11 g.) and morpholine(30 ml.) were refluxed for 16 hours, cooled, acetic acid (170 ml.) andconcentrated hydrochloric acid (280 ml.) were added and the mixture wasrefluxed for a further 7 hours. The mixture was concentrated in vacuo toremove acetic acid and the concentrate was diluted with Water. The oilwhich separated was isolated with ether, the ethereal solution wasextracted with aqueous sodium carbonate and this extract was acidifiedwith hydrochloric acid. The oil was isolated with ether, evaporated todryness and the residue was esterified by refluxing with ethanol (100ml.) and concentrated sulphuric acid (3 ml.) for hours. The excessalcohol was distilled off, the residue was diluted with water, and theoil which separated was isolated with ether. The ethereal solution waswashed with sodium carbonate solution; then with water and was dried.The ether was evaporated off and the oil was distilled to give ethyl4-s-butylphenylacetate B.P. 114-116 C./1.5 mm. (Found: C, 76.4; H, 9.0.C H O requires C, 76.4; H, 9.1%).

Ethyl 4-s-butylphenylacetate (7.8 g.) was refluxed for 1 hour withsodium hydroxide solution (5 N 10 ml.) and methanol (10 ml.), acidifiedwith hydrochloric acid and the oil which separated was isolated withether. The ethereal solution was washed with water, dried and distilledto give 4-s-butylphenylacetic acid B.P. 134 C./ 0.5 mm. (Found: C, 74.9;H, 8.5. C H O requires C, 75.0; H, 8.3%.)

In a similar manner the following compound was prepared from theappropriate ester.

4-t-pentylphenyl-acetic acid B.P. 156 C./2.5 mm. (Found: C, 75.6; H,8.6. C H O requires C, 75.8; H, 8.7%.)

Example 3 4-t-butylphenylacetyl chloride (10.5 g.) was added heated onthe steam bath for minutes. The product 8 was distilled to give as acolourless oil butyl 4-t-butylphenylacetate B.P. 126 C./ 1 mm. (Found:C, 77.7; H, 9.6. C H O requires C, 77.4; H, 9.7%.)

Similarly there was prepared:

112 C./1 mm. C H O requires C, 77.0;

Example 4 4-t-butylphenylacetamide (12.3 g.) was placed in a Soxhletextractor and extracted with boiling ether into a solution of lithiumaluminium hydride (3.0 g.) in dry ether (500 ml.). After refluxing for 6hours the mixture was decomposed with water and the ethereal filtratefrom aluminium hydroxide was extracted with very dilute hydrochloricacid. The aqueous solution was basified with sodium hydroxide solution(5 N) and the oil isolated in ether and distilled to give2-4'-t-butylphenylethylamine B.P. 92 C./2 mm. as a colourless oil.(Found: C, 81.0; H, 11.0; N, 7.6. C H N requires C, 81.3; H, 10.7; N,7.9%.)

Example 5 Sodium ethoxide from sodium (3.67 g.) in absolute alcohol (64ml.) was added over 20 minutes with stirring to a mixture of ethyl4-t-butylphenylacetate (28.14 g.) and ethyl carbonate (102 ml.) at C.The reaction flask was fitted with a Fenske column through which alcoholand then ethyl carbonate distilled. After 1 hour when the still headreached 124 C. heating was discontinued. Glacial acetic acid (12 ml.)and water (50 ml.) was added to the stirred ice cooled mixture and theester isolated in ether, washed with sodium carbonate solution, waterand distilled to give ethyl 4-t-butylphenylmalonate B.P. 144 C./1.5 mm.(Found: C, 70.4; H, 8.4. C17H24O4 requires C, 69.9; H, 8.2%.)

Ethyl 4--t-butylphenylmalonate (27.53 g.) in absolute alcohol (25 ml.)was added with stirring to a solution of sodium ethoxide from sodium(2.17 g.) in absolute alcohol (75 ml.). Ethyl iodide (15 ml.) Was addedand the mixture refluxed for 2 /2 hours, the alcohol distilled and theresidue diluted with water, extracted with ether, washed with sodiumbisulphite, water, and evaporated to dryness.

The residual oil was stirred and refluxed with sodium hydroxide (75 ml.of 5 N) water (45 ml.) and SVM ml.). Within a few minutes a sodium saltseparated and after 1 hour the solid was collected, washed with ethanol,dissolved in hot water and acidified with dilute hydrochloric acid togive the c-methyl malonic acid which was collected and dried in vacuoM.P. 177-180 (dec.).

The malonic acid (9 g.) was heated to 210-220 C. in an oil bath for 20minutes until decarboxylation had ceased. The propionic acid was cooledand recrystallised from light petroleum (B.P. 60-80" C.).

Two further recrystallisations from the same solvent gave colourlessprisms of 2-4'-t-hutylphenylpropionic acid M.P. 101-1035 C. (Found: C,75.4; H, 8.7. C H O requires C, 75.8; H, 8.7%.)

In the same manner the following were prepared:

2,4-cyclohexylphenylpropionic acid M.P. 110.5-112.5 C. (Found C, 77.8;H, 8.1. C H O requires C, 77.6; H, 8.6%.)

2-4-isobutylphenylpropionic acid M.P. 75-77.5 C. (Found: C, 75.3; H,8.6. C H O requires C, 75.8; H, 8.7%.)

9 Example 6 t-Butylbenzyl chloride g.) was added slowly to magnesium(2.65 g.) and ether (45 ml.), toluene ml.) was added and the etherdistilled. Ethyl orthofor-mate (12 g.) was added dropwise with stirringat 100 C. and the temperature maintained for minutes. The mixture wascooled, decomposed with dilute hydrochloric acid and the toluene layerseparated, washed with water, evaporated and the residue refluxed with 5N sulphuric acid (75 ml.) for 1 hour. The solution was cooled, extractedwith light petroleum (62-68 C.) and the extract was shaken with aqueoussodium bisulphite solution. The solid complex was collected, washed withether, decomposed by warming with dilute sulphuric acid and the aldehydeisolated with ether and distilled to give 4-t-butylphenylacetaldehydeB.P. 130 C./ 1.5 mm. (Found C, 82.3; H, 9.4. C H O requires C, 81.8; H,9.1%.)

Example 7 Propionyl chloride (4.9 g.) was added to a mixture of2-4-t-butylphenylethanol (6 g.) and dry pyridine (6 ml.) and the mixturewas heated under anhydrous conditions for 30 minutes on the steam bath.The reaction mixture was poured into water, acidified with 5 N sulphuricacid and the oily product was collected with ether. The ether wasdistilled to give 2-4-t-butylphenylethyl propionate as an oil B.P. 1312C./1.5 mm. (Found: C, 77.8; H, 9.1. C H O requires C, 76.9; H, 9.4%.)

Example 8 4-isobutylcyclohexanone (34.28 g.) A.R. Zinc filings (16.0 g.)ethyl bromoacetate (26.5 ml.) and dry benzene (120 ml.) were warmeduntil a vigorous reaction set in which required external cooling. Themixture was then refluxed for 30 minutes, decomposed with ice colddilute sulphuric acid, the benzene solution separated, washed withwater, dried and evaporated. The residue (49 g.) dry pyridine ml.) dryether (93 ml.) were stirred with ice cooling and thionyl chloride (26ml.) added dropwise over 30 minutes, the temperature being held below 12C. After stirring for 2 hours at 0 C., water was cautiously added to thereaction mixture, the ethereal solution was washed with water, dried andethyl 4-isobutylcyclohex-l-enylacetate was distilled; B.P. 106109 C./2mm. (Found: C, 75.0; H, 10.4. C H O requires C, 75.0; H, 10.7%.)

Ethyl 4-isobutylcyclohex-l-enylacetate (8.0 g.) and sulphur (2.7 g.)were heated at 210 for 5 hours, then at 240 C. for 2 hours. Copperpowder (100 mg.) was added and the heating continued for 5 minutes; themixture was cooled, diluted with ether, filtered and ethyl 4-isobutylphenylacetate was distilled; B.P. 110 C./1 mm. (Found: C, 76.7;H, 9.2. C I-1 0 requires C., 76.4; H, 9.1%.)

Example 9 4-isobutylbenzyl chloride g.), sodium cyanide (16.1 g.),alcohol (100 ml. water (30 ml.) were refluxed and stirred for 5 hours.The alcohol was distilled, the oil isolated in ether, washed with waterand distilled. B. P. 113 C./2 mm.

4-isobutylphenylacetonitrile (30 g.), alcohol (100 ml.), 5 N sodiumhydroxide ml.) were refluxed for 6 hours and the alcohol removed bydistillation. The residue was acidified Wtih dilute hydrochloric acidand the precipitate collected in either, extracted with dilute sodiumcarbonate solution, and the extracts acidified with dilute hydrochloricacid. The crystalline precipitate of 4-isobutylphenylacetic acid wascollected, washed with water dried in vacuo and recrystallised fromlight petroleum.

Example 1 0 To an ice cold stirred solution of anhydrous aluminumchloride (40.0 g.) in nitrobenzene (125 ml.) was slowly added ethyloxalyl chloride (27.4 g.) followed by the dropwise addition of isobutylbenzene (35 g.). After stirring for 5 hours at room temperature themixture was decomposed wtih cracked ice, ether (200 ml.) added and theorganic phase washed with sodium hydrogen carbonate solution, water anddistilled; B.P. 155 C./ 3 mm.

Ethyl 4-isobutylphenylglyoxylate (11.0 g.) was hydrogenated at roomtemperature and 2 atmospheres of hydrogen in the presence of palladiumblack (1.0 g.) and glacial acetic acid ml.). When absorption of hydrogenhad ceased, perchloric acid (7 g. of 70%) was added and hydrogenationcontinued until absorption was complete. The filtrate from the catalystwas treated with aqueous sodium hydroxide to neutralise the perchloricacid and acetic was distilled in vacuo below 50 C. The residue washydrolysed by refluxing and stirring with 2 N sodium hydroxide (50 ml.)for 6 hours, cooled and acidified with dilute hydrochloric acid, theprecipitate of 4-isobutylpheny1acetic acid collected, washed with water,dried in vacuo and recrystallised from light petroleum; (B.P. 62-68 C.).

Example 11 BENZYLAMINE 4-t-BUTYLPHENYLACTATE 4-t-butylphenylacetic acid(1.35 g.) and benzylamine (0.75 g.) were mixed in ether (30 ml.) and thesalt collected and recrystallised from absolute alcohol in colourlessplates; M.P. 144 147 C. (Found: N, 4.8. C19H25NO2 requires N, 4.7%.)

Example 12 DIETHYLAMINOETHYL d-t-BUTYLPHENYLACETATEN,N-diethylaminoethanol (10.0 g.) in dry ether (50 cc.) was addeddropwise to a stirred solution of 4-t-butylphenylacetyl chloride (15.0g.) in dry ether cc.) at 05 C. After stirring for 1 hour at roomtemperature, water (20 cc.) was added and the ether extracted twice with2 N hydrochloric acid. The aqueous solutions were combined, basifiedwith 2 N sodium hydroxide and the oil isolated in ether Washed withwater, dried and distilled B.P. 156160 C./1.5 mm. 8.5 g., 34%.Re-distilled to give a practically colourless liquid B.P. 153154 C./ 1.5mm. (Found: N, 5.2. C H NO requires N, 4.8%.)

Example 13 2-4-ISOBUTYLPHENYLETHANOL Ethyl 4-isobutylphenylacetate (15g.) in dry ether (50 ml.) was added dropwise to a stirred solution oflithium aluminium hydride (3 g.) in ether (150 ml.). The mixture wasrefluxed for 1 hour, decomposed with dilute sulphuric acid; the etherwas separated and washed with water, dried and distilled to give2-4-isobutylphenylethanol; B.P. 104 C./0.8 mm. (Found: C, 80.3; H, 10.2.CHI-I requires C, H,

Example 14 ETHYL 4-ISOBUTYLPHENYLACETATE 4-isobutylphenylacetic acid (75g.), absolute alcohol (500 ml.) and concentrated sulphuric acid (15 ml.)were refluxed for 4 hours. Excess alcohol was distilled in vacuo, theresidue diluted with water and the ester was isolated in ether, washedwith sodium carbonate solution, then water before being dried anddistilled; its B.P. was 108110 C./0.6 mm. (Found: C, 76.7; H, 9.2. C I-10 requires C, 76.4; H, 9.1%.)

In the same manner the following compounds were made:

Ethyl 4-cyclohexylphenylacetate; B.P. C./l mm. (Found: C, 78.5; H, 9.2.C H O requires C. 78.0; H, 8.9%.)

Ethyl 2-4'-isobutylphenylpropionate; B.P. 107 C./1 mm. (Found: C, 76.8;H, 9.6. C H O requires C, 77.0; H, 9.4%.)

1 1 Example 15 An intimate mixture was prepared of equal parts of4-isobutylphenylacetic acid and a tablet base comprising starch with theaddition of 1% magnesium stearate as a lubricant. The mixture wascompressed into tablets containing 2 /2 grains of 4-isobutylphenylaceticacid.

Similar tablets were also prepared but using as the active ingredientother compounds of the present invention such as4-isobutylphenylpropionic acid or 4-cyclohexylphenylacetic acid.

Example 16 An intimate mixture was made of parts of4-isobutylphenylacetic acid and 3 parts of a tablet base comprisingstarch with the addition of 1% magnesium stearate as a lubricant. Themixture was compressed into tablets containing 5 grains of4-isobutylphenylacetic acid.

Similar tablets were also prepared but using as the active ingredientother compounds of the invention such as 4-isobutylphenylpropionic acidor 4-cyclohexylphenylacetic acid.

Example 17 A mixture Was prepared from the following ingredients:

Sodium 4-isobutylphenylacetate g 13.7 Concentrated orange peel infusionml 62.5 Chloroform water to ml 1,000

A dose of the above mixture is contained in 15 ml.

Example 18 A suspension was prepared from the following ingredients:

1. A method of alleviating the symptoms of inflammation which comprisesadministering to an animal suffering such symptoms between 1 and 100grains daily of a compound of the formula:

wherein R is selected from the group consisting of ethyl, propyl,branched C and C alkyl, C and C alkyloxy, allyloxy, phenoxy, phenylthio,C to C cycloalkyl and C to C7 cycloalkyl substituted in the one positionby a C to C akyl, R is selected from the group consisting of hydrogenand methyl; X is selected from the group consisting of -COOR COOM, COOHBand CH .O wherein R is selected from the group consisting of hydrogenand C to C alkyl, M is selected from the group consisting of NH; and asingle equivalent of a non-toxic metallic cation and B is a non-toxicorganic base.

2. The method of claim 1 in which the inflammation is inflammation ofthe connective tissue and the amount of said compound administered tothe animal daily is between 5 and 100 grains.

3. The method of claim 2 in which the inflammation is that of rheumatoidarthritis.

4. The method of claim 2 in which the inflammation is that of rheumaticfever.

5. A method of alleviating the symptoms of pain which comprisesadministering to an animal suffering such symptoms between 1 and grainsdaily of a compound of the formula:

wherein R is selected from the group consisting of ethyl, propyl,branched C and C alkyl, C and C alkyloxy, allyloxy, phenoxy, phenylthio,C to C cycloalkyl and C to C cycloalkyl substituted in the one positionby a C to C alkyl; R is selected from the group consisting of hydrogenand methyl; X is selected from the group consisting of COOR COOM, COOHBand CH .OH wherein R is selected from the group consisting of hydrogenand C to C alkyl, M is selected from the group consisting of NH; and asingle equivalent of a non-toxic metallic cation and B is a non-toxicorganic base.

6. A method of alleviating the symptoms of fever which comprisesadministering to an animal suffering such symptoms between 1 and 100grains daily of a compound of the formula:

wherein R is selected from the group consisting of ethyl, propyl,branched C and C alkyl, C and C alkoxy, allyloxy, phenoxy, phenylthio, Cto C cycloalkyl and C to C cycloalkyl substituted in the one position bya C to C alkyl; R is selected from the group consisting of hydrogen andmethyl; X is selected from the group consisting of COOR COOM, COOH.B andCH .OH wherein R is selected from the group consisting of hydrogen and Cto C alkyl, M is selected from the group consisting of NH; and a singleequivalent of a non-toxic metallic cation and B is a non-toxic organicbase.

7. A therapeutic composition in dosage form adapted for therapeuticadministration comprising per unit as active ingredient 25500 mg. of acompound of the formula:

wherein R is selected from the group consisting of ethyl, propyl,branched C and C alkyl, C and C alkyloxy, allyloxy, phenoxy, phenylthio,C to C cycloalkyl and C to C cycloalkyl substituted in the one positionby a C to C alkyl; R is selected from the group consisting of hydrogenand methyl; X is selected from the group consisting of COOR COOM,COOl-LB and -CH .OH where R is selected from the group consisting ofhydrogen and C to C alkyl, M is selected from the group consisting ofNH; and a single equivalent of a non-toxic metallic cation and E is anon-toxic organic base, in association with a pharmaceuticallyacceptable carrier.

8. The composition according to claim 7 in which the pharmaceuticallyeffective carrier comprises starch and magnesium stearate.

9. A therapeutic composition in dosage unit form comprising per unit 25to 500 mg. of 4-isobutylphenyl acetic acid and a pharmaceuticallyacceptable carrier.

10. A therapeutic composition in dosage unit form comprising per unit 25to 500 mg. of a non-toxic salt of 4-isobutylphenyl acetic acid and apharmaceutically acceptable carrier.

11. A tablet comprising 2 /25 grains of 4-isobutylphenylacetic acid asthe therapeutically effective ingredient associated with apharmaceutical base comprising starch and magnesium stearate.

13 12. A tablet comprising 2 /2-5 grains of sodium 4-is0-butylphenylacetate as the therapeutically efiective ingredientassociated with a pharmaceutical base comprising starch and magnesiumstearate.

References Cited by the Examiner UNITED STATES PATENTS 3,046,305 7/ 1962Braunwarth 260-515 3,047,462 7/1962 Mail-lard et a1. 167-65 3,047,4647/1962 Schaeppi 16765 3,102,135 8/1963 Petropoulos et a1. 260-515 OTHERREFERENCES Chem. Abst., (1), vol. 54, p. 21 -186(21) (1960). Chem.Abst., (2), vol. 53, p. l9305(e) (1959).

14 Chem. Abst., (3) vol. 54, p. 18499(e) (1960). Chem. Abst., (4), vol.54, p. 435(g) (1960). Chem. Abst., (5), vol. 44, p. 9375(a) (1950).Chem. Abst., (6), vol. 47, p. 3274(a) (1953). 5 Chem. Abst., (7), vol.43, p. 3361(g) (1949). Chem. Abst., (8), vol. 50, p. 1986(i) (1956).Chemical Abstracts I, vol. 42, pg. 4557d (1948) (abstract of Carter etal., J. Chem. Soc. Part I, pp. 150-155).

Chemical Abstracts II, vol. 46, pg. 1515c (1952) (ab- 10 stract ofSkinner et al., J. Am. Chem. Soc., vol. 73, pp.

FRANK CACCIAPAGLIA, 111., Primary Examiner.

15 MORRIS O. WOLK, Examiner.

1. A METHOD OF ALLEVIATING THESYMPTOMS OF INFLAMMATION WHICH COMPRISESADMINISTERING TO AN ANIMAL SUFFERING SUCH SYMPTOMS BETWEEN 1 AND 100GRAINS DAILY OF A COMPOUND OF THE FORMULA:
 7. A THERAPEUTIC COMPOSITIONIN DOSAGE FORM ADAPTED FOR THERAPEUTIC ADMINISTRATION COMPRISING PERUNIT AS ACTIVE INGREDIENT 25-500 MG. OF A COMPOUND OF THE FORMULA: